Summary This will be the first combined therapeutic HIV vaccine study in pediatrics. Our goal is to develop therapeutic HIV vaccines to reduce the HIV reservoirs in children and youth with HIV. Our scientific premise is that the prime-boost HIVIS DNA and MVA-CMDR vaccines induce cellular and humoral immune responses important for clearing infected cells. They were selected for children based on ample adult safety data. We include early treated children because of their healthy immunity and small HIV reservoirs. Other novel components include giving a licensed vaccine against human papilloma virus that contains toll-like receptor (TLR) 4 agonist adjuvant to boost immune responses to HIVIS DNA. We will also give MVA-CMDR to the only 10 HIV-infected children worldwide that previously had HIVIS DNA as this late boost strategy was shown in adults to enhance immunity to vaccines. We will include children from South Africa, Thailand and Italy infected with different clades of HIV - a strength that will support the generalizability of the results to the global epidemic. The project will be conducted under the umbrella of the EPIICAL Consortium and the US. Military HIV Research Program that is dedicated to developing therapeutic HIV vaccines as a strategy towards an HIV remission. Thirty-five participants will be in this 48-week study including 25 that are 9 to 18 years old who started HIV medications prior to 6 months of age and are virally suppressed. They will be randomly assigned to HIV vaccines (n=10) vs. HIV vaccines+TLR4 agonist (n=10) vs. control (no interventions) (n=5). Vaccines will be given at weeks 0, 4 and 12 for HIVIS DNA and TLR4 agonist, and weeks 24 and 36 for MVA-CMDR. The MVA-CMDR late boost 7 years after HIVIS DNA will be evaluated in 10 Italian youth aged 14 to 24 years old. We will extensively measure the changes of HIV reservoirs and immune responses post interventions. Aim 1: To quantitate and characterize the HIV reservoirs before and after HIVIS DNA TLR4 agonist and MVA-CMDR vaccination Aim 2: To characterize HIV-specific cellular and humoral immune responses before and after vaccination and assess their relationship to the HIV reservoir endpoints. Aim 3: To quantitate and characterize the immunogenicity and HIV reservoir endpoints in youth previously vaccinated with HIVIS DNA and receiving MVA-CMDR late boost. The knowledge generated will contribute to the optimization of therapeutic HIV vaccine strategies and exert sustained influence on HIV cure research for children and youth.